Rationale: Male gender is an important risk factor for progression of diabetic nephropathy, the leading cause of end-stage renal disease. Mechanisms by which the relative ratio of estrogen to androgen specifically impacts renal dysfunction and fibrosis are not well defined. There is strong rationale to study gender hormones: to understand the mechanisms by which estrogens protect, and/or androgens injure, the kidney; to utilize recent advances in the vascular biology of gender hormones, as they pertain to the kidney; and to determine the utility of new hormonal derivatives which may be safer and free of side effects, in both men and women. Many cellular actions of sex steroids have not been tested in the kidney, and are likely to differentially affect the discrete intrarenal compartments (glomerular/vascular vs. tubulointerstitial) which play a role in loss of renal function. We will explore the role of classical and novel gender hormones in experimental diabetes. To achieve our aims, we will use complementary physiological, biochemical, molecular, and immunohistochemical approaches, joining in vivo and in vitro studies. Hypotheses: (1) Gender-related protection against diabetic nephropathy is related to the protective effect of endogenous estrogen and its metabolites; (2) estrogenic compounds limit the activity of the renin-angiotensin system (RAS), and act synergistically with drugs which block the RAS; (3) estrogenic compounds shift the balance in endothelial-derived vasoactive mediators, with a net increase in nitric oxide (NO) action, and reduction in endothelin-1 (ET); and (4) actions of gender hormones relate in part relate to their effects on vascular endothelial growth factor (VEGF), and its interactions with fibrotic mediators. Specific Aims: In experimental diabetes, (1) to determine the contribution of gender to susceptibility to diabetic glomerular and tubulointerstitial injury, and whether manipulation of gender hormones alters the course of disease; (2) to examine the interactions among gender hormones and the renin-angiotensin system on hemodynamics, vasoactive mediators, and fibrosis mediators; (3) to examine the interactions among gender hormones and the nitric oxide/endothelin systems, on hemodynamics, vasoactive mediators, and fibrosis mediators; and (4) to determine the role of VEGF in altering the balance of matrix forming and degrading enzymes in experimental diabetes.